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Role of the Histamine H3 Receptor in the Central Nervous System

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Histamine and Histamine Receptors in Health and Disease

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 241))

Abstract

The Gi/o protein-coupled histamine H3 receptor is distributed throughout the central nervous system including areas like cerebral cortex, hippocampus and striatum with the density being highest in the posterior hypothalamus, i.e. the area in which the histaminergic cell bodies are located. In contrast to the other histamine receptor subtypes (H1, H2 and H4), the H3 receptor is located presynaptically and shows a constitutive activity. In detail, H3 receptors are involved in the inhibition of histamine release (presynaptic autoreceptor), impulse flow along the histaminergic neurones (somadendritic autoreceptor) and histamine synthesis. Moreover, they occur as inhibitory presynaptic heteroreceptors on serotoninergic, noradrenergic, dopaminergic, glutamatergic, GABAergic and perhaps cholinergic neurones. This review shows for four functions of the brain that the H3 receptor represents a brake against the wake-promoting, anticonvulsant and anorectic effect of histamine (via postsynaptic H1 receptors) and its procognitive activity (via postsynaptic H1 and H2 receptors). Indeed, H1 agonists and H3 inverse agonists elicit essentially the same effects, at least in rodents; these effects are opposite in direction to those elicited by brain-penetrating H1 receptor antagonists in humans. Although the benefit for H3 inverse agonists for the symptomatic treatment of dementias is inconclusive, several members of this group have shown a marked potential for the treatment of disorders associated with excessive daytime sleepiness. In March 2016, the European Commission granted a marketing authorisation for pitolisant (WakixR) (as the first representative of the H3 inverse agonists) for the treatment of narcolepsy.

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References

  • Anichtchik OV, Peitsaro N, Rinne JO, Kalimo H, Panula P (2001) Distribution and modulation of histamine H3 receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson’s disease. Neurobiol Dis 8:707–716

    Article  CAS  PubMed  Google Scholar 

  • Arrang JM, Garbarg M, Schwartz JC (1983) Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 302:832–837

    Article  CAS  PubMed  Google Scholar 

  • Arrang JM, Garbarg M, Schwartz JC (1987a) Auto-inhibition of histamine synthesis mediated by presynaptic H3-receptors. Neuroscience 23:149–157

    Article  CAS  PubMed  Google Scholar 

  • Arrang JM, Garbarg M, Lancelot JC, Lecomte JM, Pollard H, Robba M, Schunack W, Schwartz JC (1987b) Highly potent and selective ligands for histamine H3-receptors. Nature 327:117–123

    Article  CAS  PubMed  Google Scholar 

  • Arrang JM, Devaux B, Chodkiewicz JP, Schwartz JC (1988) H3-Receptors control histamine release in human brain. J Neurochem 51:105–108

    Article  CAS  PubMed  Google Scholar 

  • Bhowmik M, Khanam R, Vohora D (2012) Histamine H3 receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives. Br J Pharmacol 167:1398–1414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonaventure P, Letavic M, Dugovic C, Wilson S, Aluisio L, Pudiak C, Lord B, Mazur C, Kamme F, Nishino S, Carruthers N, Lovenberg T (2007) Histamine H3 receptor antagonists: from target identification to drug leads. Biochem Pharmacol 73:1084–1096

    Article  CAS  PubMed  Google Scholar 

  • Bongers G, Krueger KM, Miller TR, Baranowski JL, Estvander BR, Witte DG, Strakhova MI, van Meer P, Bakker RA, Cowart MD, Hancock AA, Esbenshade TA, Leurs R (2007) An 80-amino acid deletion in the third intracellular loop of a naturally occurring human histamine H3 isoform confers pharmacological differences and constitutive activity. J Pharmacol Exp Ther 323:888–898

    Article  CAS  PubMed  Google Scholar 

  • Brown RE, Haas HL (1999) On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyrus. J Physiol 515:777–786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chazot PL, Hann V, Wilson C, Lees G, Thompson CL (2001) Immunological identification of the mammalian H3 histamine receptor in the mouse brain. Neuroreport 12:259–262

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Sugimoto Y, Kamei C (1999) Effects of intracerebroventricular injection of α-fluoromethylhistidine on radial maze performance in rats. Pharmacol Biochem Behav 64:513–518

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Li WD, Zhu LJ, Shen YJ, Wei EQ (2002) Effects of histidine, a precursor of histamine, on pentylenetetrazole-induced seizures in rats. Acta Pharmacol Sin 23:361–366

    CAS  PubMed  Google Scholar 

  • Chen Z, Li Z, Sakurai E, Mobarakeh JI, Ohtsu H, Watanabe T, Watanabe T, Iinuma K, Yanai K (2003) Chemical kindling induced by pentylenetetrazol in histamine H1 receptor gene knockout mice (H1KO), histidine decarboxylase-deficient mice (HDC–/–) and mast cell-deficient W/Wv mice. Brain Res 968:162–166

    Article  CAS  PubMed  Google Scholar 

  • Clapp RH, Luckman SM (2012) Proxyfan acts as a neutral antagonist of histamine H3 receptors in the feeding-related hypothalamic ventromedial nucleus. Br J Pharmacol 167:1099–1110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clark EA, Hill SJ (1996) Sensitivity of histamine H3 receptor agonist-stimulated [35S] GTP gamma[S] binding to pertussis toxin. Eur J Pharmacol 296:223–225

    Article  CAS  PubMed  Google Scholar 

  • Dai H, Kaneko K, Kato H, Fujii S, Jing Y, Xu A, Sakurai E, Kato M, Okamura N, Kuramasu A, Yanai K (2007) Selective cognitive dysfunction in mice lacking histamine H1 and H2 receptors. Neurosci Res 57:306–313

    Article  CAS  PubMed  Google Scholar 

  • Dauvilliers Y, Bassetti C, Lammers GJ, Arnulf I, Mayer G, Rodenbeck A, Lehert P, Ding CL, Lecomte JM, Schwartz JC, Harmony I study group (2013) Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol 12:1068–1075

    Google Scholar 

  • De Luca R, Suvorava T, Yang D, Baumgärtel W, Kojda G, Haas HL, Sergeeva O (2016) Identification of histaminergic neurons through histamine 3 receptor-mediated autoinhibition. Neuropharmacology 106:102–115

    Article  PubMed  CAS  Google Scholar 

  • Dere E, De Souza Silva MA, Topic B, Spieler RE, Haas HL, Huston JP (2003) Histidine-decarboxylase knockout mice show deficient nonreinforced episodic object memory, improved negatively reinforced water-maze performance, and increased neo- and ventro-striatal dopamine turnover. Learn Mem 10:510–519

    Article  PubMed  PubMed Central  Google Scholar 

  • Dere E, Zlomuzica A, Viggiano D, Ruocco LA, Watanabe T, Sadile AG, Huston JP, De Souza Silva MA (2008) Episodic-like and procedural memory impairments in histamine H1 receptor knockout mice coincide with changes in acetylcholine esterase activity in the hippocampus and dopamine turnover in the cerebellum. Neuroscience 157:532–541

    Article  CAS  PubMed  Google Scholar 

  • Dimitriadou V, Rouleau A, Tuong MDT, Newlands GJF, Miller HRP, Luffau G, Schwartz JC, Garbarg M (1994) Functional relationship between mast cells and C-sensitive nerve fibres evidenced by histamine H3-receptor modulation in rat lung and spleen. Clin Sci 87:151–163

    Article  CAS  PubMed  Google Scholar 

  • Doreulee N, Yanovsky Y, Flagmeyer I, Stevens DR, Haas HL, Brown RE (2001) Histamine H3 receptors depress synaptic transmission in the corticostriatal pathway. Neuropharmacology 40:106–113

    Article  CAS  PubMed  Google Scholar 

  • Drutel G, Peitsaro N, Karlstedt K, Wieland K, Smit MJ, Timmerman H, Panula P, Leurs R (2001) Identification of rat H3 receptor isoforms with different brain expression and signaling properties. Mol Pharmacol 59:1–8

    CAS  PubMed  Google Scholar 

  • Egan M, Yaari R, Liu L, Ryan M, Peng Y, Lines C, Michelson D (2012) Pilot randomized controlled study of a histamine receptor inverse agonist in the symptomatic treatment of AD. Curr Alzheimer Res 9:481–490

    Article  CAS  PubMed  Google Scholar 

  • Ellenbroek BA, Ghiabi B (2014) The other side of the histamine H3 receptor. Trends Neurosci 37:191–199

    Article  CAS  PubMed  Google Scholar 

  • European Medicines Agency (2016) Wakix. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002616/human_med_001955.jsp&mid=WC0b0lac058001d124. Accessed 15 Aug 2016

  • Ferrada C, Ferré S, Casadó V, Cortés A, Justinova Z, Barnes C, Canela EI, Goldberg SR, Leurs R, Lluis C, Franco R (2008) Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function. Neuropharmacology 55:190–197

    Article  CAS  PubMed  Google Scholar 

  • Ferrada C, Moreno E, Casadó V, Bongers G, Cortés A, Mallol J, Canela EI, Leurs R, Ferré S, Lluís C, Franco R (2009) Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors. Br J Pharmacol 157:64–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feuerstein TJ (2008) Presynaptic receptors for dopamine, histamine and serotonin. Handb Exp Pharmacol 184:289–338

    Article  CAS  Google Scholar 

  • Garbarg M, Arrang M, Rouleau A, Ligneau X, Tuong MDT, Schwartz JC, Ganellin CR (1992) S-[2-(4-imidazolyl)ethyl]isothiourea, a highly specific and potent histamine H3 receptor agonist. J Pharmacol Exp Ther 263:304–310

    CAS  PubMed  Google Scholar 

  • Gbahou F, Rouleau A, Morisset S, Parmentier R, Crochet S, Lin JS, Ligneau X, Tardivel-Lacombe J, Stark H, Schunack W, Ganellin CR, Schwartz JC, Arrang JM (2003) Protean agonism at histamine H3 receptors in vitro and in vivo. Proc Natl Acad Sci 100:11086–11091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gbahou F, Davenas E, Morisset S, Arrang JM (2010) Effects of betahistine at histamine H3 receptors: Mixed inverse agonism/agonism in vitro and partial inverse agonism in vivo. J Pharmacol Exp Ther 334:945–954

    Article  CAS  PubMed  Google Scholar 

  • Giovannini MG, Efoudebe M, Passani MB, Baldi E, Bucherelli C, Giachi F, Corradetti R, Blandina P (2003) Improvement in fear memory by histamine-elicited ERK2 activation in hippocampal CA3 cells. J Neurosci 23:9016–9023

    CAS  PubMed  Google Scholar 

  • Gondard E, Anaclet C, Akaoka H, Guo RX, Zhang M, Buda C, Franco P, Kotani H, Lin JS (2013) Enhanced histaminergic neurotransmission and sleep-wake alterations, a study in histamine H3-receptor knock-out mice. Neuropsychopharmacology 38:1015–1031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grove RA, Harrington CM, Mahler A, Beresford I, Maruff P, Lowy MT, Nicholls AP, Boardley RL, Berges AC, Nathan PJ, Horrigan JP (2014) A randomized, double-blind, placebo-controlled, 16-week study of the H3 receptor antagonist, GSK239512 as a monotherapy in subjects with mild-to-moderate Alzheimer’s disease. Curr Alzheimer Res 11:47–58

    Article  CAS  PubMed  Google Scholar 

  • Haas HL, Sergeeva OA, Selbach O (2008) Histamine in the nervous system. Physiol Rev 88:1183–1241

    Article  CAS  PubMed  Google Scholar 

  • Haig GM, Pritchett Y, Meier A, Othman AA, Hall C, Gault LM, Lenz RA (2014) A randomized study of H3 antagonist ABT-288 in mild-to-moderate Alzheimer’s dementia. J Alzheimers Dis 42:959–971

    CAS  PubMed  Google Scholar 

  • Hancock AA, Esbenshade TA, Krueger KM, Yao BB (2003) Genetic and pharmacological aspects of histamine H3 receptor heterogeneity. Life Sci 73:3043–3072

    Article  CAS  PubMed  Google Scholar 

  • Hirai T, Okuma C, Harada C, Mio M, Ohtsu H, Watanabe T, Kamei C (2004) Development of amygdaloid kindling in histidine decarboxylase-deficient and histamine H1 receptor-deficient mice. Epilepsia 45:309–313

    Article  CAS  PubMed  Google Scholar 

  • Hough LB (1988) Cellular localization and possible functions for brain histamine: recent progress. Prog Neurobiol 30:469–505

    Article  CAS  PubMed  Google Scholar 

  • Howlett AC (2005) Cannabinoid receptor signaling. Handb Exp Pharmacol 168:53–79

    Article  CAS  Google Scholar 

  • Iinuma K, Yokoyama H, Otsuki T, Yanai K, Watanabe T, Ido T, Itoh M (1993) Histamine H1 receptors in complex partial seizures. Lancet 341:238

    Article  CAS  PubMed  Google Scholar 

  • Jansen FP, WU TS, Voss HP, Steinbusch HWM, Vollinga RC, Rademaker B, Bast A, Timmerman H (1994) Characterization of the binding of the first selective radiolabelled histamine H3-receptor antagonist, [125I]iodophenpropit, to rat brain. Brit J Pharmacol 113:355–362

    Google Scholar 

  • Jin CY, Panula P (2005) The laminar histamine receptor system in human prefrontal cortex suggests multiple levels of histaminergic regulation. Neuroscience 132:137–149

    Article  CAS  PubMed  Google Scholar 

  • Jin CY, Kalimo H, Panula P (2002) The histaminergic system in human thalamus: correlation of innervation to receptor expression. Eur J Neurosci 15:1125–1138

    Article  CAS  PubMed  Google Scholar 

  • Jin CL, Zhuge ZB, Wu DC, Zhu YY, Wang S, Luo JH, Chen Z (2007) Lesion of the tuberomammillary nucleus E2-region attenuates postictal seizure protection in rats. Epilepsy Res 73:250–258

    Article  PubMed  Google Scholar 

  • Jones BE (2005) From waking to sleeping: neuronal and chemical substrates. Trends Pharmacol Sci 26:578–586

    Article  CAS  PubMed  Google Scholar 

  • Jørgensen EA, Knigge U, Watanabe T, Warberg J, Kjaer A (2005) Histaminergic neurons are involved in the orexigenic effect of orexin-A. Neuroendocrinology 82:70–77

    Article  PubMed  CAS  Google Scholar 

  • Kubista H, Boehm S (2006) Molecular mechanisms underlying the modulation of exocytotic noradrenaline release via presynaptic receptors. Pharmacol Ther 112:213–242

    Article  CAS  PubMed  Google Scholar 

  • Kukko-Lukjanov TK, Lintunen M, Jalava N, Lauren HB, Lopez-Picon FR, Michelsen KA, Panula P, Holopainen IE (2010) Involvement of histamine 1 receptor in seizure susceptibility and neuroprotection in immature mice. Epilepsy Res 90:8–15

    Article  CAS  PubMed  Google Scholar 

  • Kukko-Lukjanov TK, Gronman M, Lintunen M, Lauren HB, Michelsen KA, Panula P, Holopainen IE (2012) Histamine 1 receptor knock out mice show age-dependent susceptibility to status epilepticus and consequent neuronal damage. Epilepsy Res 100:80–92

    Article  CAS  PubMed  Google Scholar 

  • Lamberty Y, Margineanu DG, Dassesse D, Klitgaard H (2003) H3 agonist immepip markedly reduces cortical histamine release, but only weakly promotes sleep in the rat. Pharmacol Res 48:193–198

    Article  CAS  PubMed  Google Scholar 

  • Łażewska D, Kieć-Kononowicz K (2014) New developments around histamine H3 receptor antagonists/inverse agonists: a patent review (2010 - present). Expert Opin Ther Pat 24:89–111

    Article  PubMed  CAS  Google Scholar 

  • Lecklin A, Tuomisto L (1998) The blockade of H1 receptors attenuates the suppression of feeding and diuresis induced by inhibition of catabolism. Pharmacol Biochem Behav 59:753–758

    Article  CAS  PubMed  Google Scholar 

  • Leurs R, Bakker RA, Timmerman H, de Esch IJP (2005) The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov 4:107–120

    Article  CAS  PubMed  Google Scholar 

  • Leu-Semenescu S, Nittur N, Golmard JL, Arnulf I (2014) Effects of pitolisant, a histamine H3 inverse agonist, in drug-resistant idiopathic and symptomatic hypersomnia: a chart review. Sleep Med 15:681–687

    Article  PubMed  Google Scholar 

  • Liblau RS, Vassalli A, Seifinejad A, Tafti M (2015) Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy. Lancet Neurol 14:318–328

    Article  CAS  PubMed  Google Scholar 

  • Liedtke S, Flau K, Kathmann M, Schlicker E, Stark H, Meier G, Schunack W (2003) Replacement of imidazole by a piperidine moiety differentially affects the potency of histamine H3-receptor antagonists. Naunyn Schmiedebergs Arch Pharmacol 367:43–50

    Article  CAS  PubMed  Google Scholar 

  • Ligneau X, Garbarg M, Vizuete ML, Diaz J, Purand K, Stark H, Schunack W, Schwartz JC (1994) [125I]Iodoproxyfan, a new antagonist to label and visualize cerebral histamine H3 receptors. J Pharmacol Exp Ther 271:452–459

    CAS  PubMed  Google Scholar 

  • Ligneau X, Morisset S, Tardivel-Lacombe J, Gbahou F, Ganellin CR, Stark H, Schunack W, Schwartz JC, Arrang JM (2000) Distinct pharmacology of rat and human histamine H3 receptors: role of two amino acids in the third transmembrane domain. Br J Pharmacol 131:1247–1250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin JS (2000) Brain structures and mechanisms involved in the control of cortical activation and wakefulness, with emphasis on the posterior hypothalamus and histaminergic neurons. Sleep Med Rev 4:471–503

    Article  CAS  PubMed  Google Scholar 

  • Lin JS, Sakai K, Vanni-Mercier G, Arrang JM, Garbarg M, Schwartz JC, Jouvet M (1990) Involvement of histaminergic neurons in arousal mechanisms demonstrated with H3-receptor ligands in the cat. Brain Res 523:325–330

    Article  CAS  PubMed  Google Scholar 

  • Lin JS, Dauvilliers Y, Arnulf I, Bastuji H, Anaclet C, Parmentier R, Kocher L, Yanagisawa M, Lehert P, Ligneau X, Perrin D, Robert P, Roux M, Lecomte JM, Schwartz JC (2008) An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: studies in orexin–/– mice and patients. Neurobiol Dis 30:74–83

    Article  PubMed  CAS  Google Scholar 

  • Lin JS, Sergeeva OA, Haas HL (2011) Histamine H3 receptors and sleep-wake regulation. J Pharmacol Exp Ther 336:17–23

    Article  CAS  PubMed  Google Scholar 

  • Lippert U, Artuc M, Grützkau A, Babina M, Guhl S, Haase I, Blaschke V, Zachmann K, Knosalla M, Middel P, Krüger-Krasagakis S, Henz BM (2004) Human skin mast cells express H2 and H4, but not H3 receptors. J Invest Dermatol 123:116–123

    Article  CAS  PubMed  Google Scholar 

  • Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR, Erlander MG (1999) Cloning and functional expression of the human histamine H3 receptor. Mol Pharmacol 55:1101–1107

    CAS  PubMed  Google Scholar 

  • Lundius EG, Sanchez-Alavez M, Ghochani Y, Klaus J, Tabarean IV (2010) Histamine influences body temperature by acting at H1 and H3 receptors on distinct populations of preoptic neurons. J Neurosci 30:4369–4381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malmberg-Aiello P, Ipponi A, Bartolini A, Schunack W (2000) Antiamnesic effect of metoprine and of selective histamine H1 receptor agonists in a modified mouse passive avoidance test. Neurosci Lett 288:1–4

    Article  CAS  PubMed  Google Scholar 

  • Malmlöf K, Hastrup S, Wulff BS, Hansen BC, Peschke B, Jeppesen CB, Hohlweg R, Rimvall K (2007) Antagonistic targeting of the histamine H3 receptor decreases caloric intake in higher mammalian species. Biochem Pharmacol 73:1237–1242

    Article  PubMed  CAS  Google Scholar 

  • Masaki T, Chiba S, Yasuda T, Noguchi H, Kakuma T, Watanabe T, Sakata T, Yoshimatsu H (2004) Involvement of hypothalamic H1 receptor in the regulation of feeding rhythm and obesity. Diabetes 53:2250–2260

    Article  CAS  PubMed  Google Scholar 

  • McLeod RL, Aslanian R, Del Prado M, Duffy R, Egan RW, Kreutner W, McQuade R, Hey JA (1998) Sch 50971, an orally active histamine H3 receptor agonist, inhibits central neurogenic vascular inflammation and produces sedation in the guinea pig. J Pharmacol Exp Ther 287:43–50

    CAS  PubMed  Google Scholar 

  • Meier G, Apelt J, Reichert U, Grassmann S, Ligneau X, Elz S, Leurquin F, Ganellin CR, Schwartz JC, Schunack W, Stark H (2001) Influence of imidazole replacement in different structural classes of histamine H3-receptor antagonists. Eur J Pharm Sci 13:249–259

    Article  CAS  PubMed  Google Scholar 

  • Miyazaki S, Imaizumi M, Onodera K (1995a) Effects of thioperamide on the cholinergic system and the step-through passive avoidance test in mice. Methods Find Exp Clin Pharmacol 17:653–658

    CAS  PubMed  Google Scholar 

  • Miyazaki S, Imaizumi M, Onodera K (1995b) Effects of thioperamide, a histamine H3-receptor antagonist, on a scopolamine-induced learning deficit using an elevated plus-maze test in mice. Life Sci 57:2137–2144

    Article  CAS  PubMed  Google Scholar 

  • Monti JM, Orellana C, Boussard M, Jantos H, Olivera S (1990) Sleep variables are unaltered by zolantidine in rats: are histamine H2-receptors not involved in sleep regulation? Brain Res Bull 25:229–231

    Article  CAS  PubMed  Google Scholar 

  • Monti JM, Jantos H, Boussard M, Altier H, Orellana C, Olivera S (1991) Effects of selective activation or blockade of the histamine H3 receptor on sleep and wakefulness. Eur J Pharmacol 205:283–287

    Article  CAS  PubMed  Google Scholar 

  • Nakazi M, Bauer U, Nickel T, Kathmann M, Schlicker E (2000) Inhibition of serotonin release in the mouse brain via presynaptic cannabinoid CB1 receptors. Naunyn Schmiedebergs Arch Pharmacol 361:19–24

    Article  CAS  PubMed  Google Scholar 

  • Nathan PJ, Boardley R, Scott N, Berges A, Maruff P, Sivananthan T, Upton N, Lowy MT, Nestor PJ, Lai R (2013) The safety, tolerability, pharmacokinetics and cognitive effects of GSK239512, a selective histamine H3 receptor antagonist in patients with mild to moderate Alzheimer’s disease: a preliminary investigation. Curr Alzheimer Res 10:240–251

    Article  CAS  PubMed  Google Scholar 

  • Nickel T, Bauer U, Schlicker E, Kathmann M, Göthert M, Sasse A, Stark H, Schunack W (2001) Novel histamine H3-receptor antagonists and partial agonists with a non-aminergic structure. Br J Pharmacol 132:1665–1672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishino S, Okura M, Mignot E (2000) Narcolepsy: genetic predisposition and neuropharmacological mechanisms. Sleep Med Rev 4:57–99

    Article  PubMed  Google Scholar 

  • Ookuma K, Sakata T, Fukagawa K, Yoshimatsu H, Kurokawa M, Machidori H, Fujimoto K (1993) Neuronal histamine in the hypothalamus suppresses food intake in rats. Brain Res 628:235–242

    Article  CAS  PubMed  Google Scholar 

  • Panula P, Nuutinen S (2013) The histaminergic network in the brain: basic organization and role in disease. Nat Rev Neurosci 14:472–487

    Article  CAS  PubMed  Google Scholar 

  • Panula P, Chazot PL, Cowart M, Gutzmer R, Leurs R, Liu WLS, Stark H, Thurmond RL, Haas HL (2015) Internation Union of basic and clinical pharmacology. XCVIII. Histamine receptors. Pharmacol Rev 67:601–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parmentier R, Ohtsu H, Djebarra-Hannas Z, Valatx JL, Watanabe T, Lin JS (2002) Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. J Neurosci 22:7695–7711

    CAS  PubMed  Google Scholar 

  • Parmentier R, Anaclet C, Guhennec C, Brousseau E, Bricout D, Giboulot T, Bozyczko-Coyne D, Spiegel K, Ohtsu H, Williams M, Lin JS (2007) The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders. Biochem Pharmacol 73:1157–1171

    Article  CAS  PubMed  Google Scholar 

  • Passani MB, Blandina P, Torrealba F (2011) The histamine H3 receptor and eating behavior. J Pharmacol Exp Ther 336:24–29

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, compact, 3rd edn. Academic, San Diego

    Google Scholar 

  • Pillot C, Heron A, Cochois V, Tardivel-Lacombe J, Ligneau X, Schwartz JC, Arrang JM (2002) A detailed mapping of the histamine H3 receptor and its gene transcripts in rat brain. Neuroscience 114:173–193

    Article  CAS  PubMed  Google Scholar 

  • Pollard H, Schwartz JC (1987) Histamine neuronal pathways and their functions. Trends Neurosci 10:86–89

    Article  CAS  Google Scholar 

  • Pollard H, Moreau J, Arrang JM, Schwartz JC (1993) A detailed autoradiographic mapping of histamine H3 receptors in rat brain areas. Neuroscience 52:169–189

    Article  CAS  PubMed  Google Scholar 

  • Poyurovsky M, Fuchs C, Pashinian A, Levi A, Weizman R, Weizman A (2013) Reducing antipsychotic-induced weight gain in schizophrenia: a double-blind placebo-controlled study of reboxetine-betahistine combination. Psychopharmacol (Berl) 216:615–622

    Article  CAS  Google Scholar 

  • Provensi G, Blandina P, Passani MB (2016) The histaminergic system as a target for the prevention of obesity and metabolic syndrome. Neuropharmacology 106:3–12

    Article  CAS  PubMed  Google Scholar 

  • Rahmani RH, Ingram CD (2007) Histamine controls food intake in sheep via H1 receptors. Small Ruminant Res 70:110–115

    Article  Google Scholar 

  • Rouleau A, Ligneau X, Tardivel-Lacombe J, Morisset S, Gbahou F, Schwartz JC, Arrang JM (2002) Histamine H3-receptor-mediated [35S]GTPγS binding: evidence for constitutive activity of the recombinant and native rat and human H3 receptors. Br J Pharmacol 135:383–392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sadek B, Stark H (2016) Cherry-picked ligands at histamine receptor subtypes. Neuropharmacology 106:56–73

    Article  CAS  PubMed  Google Scholar 

  • Sadek B, Saad A, Subramanian D, Shafiullah M, Łażewska D, Kieć-Kononowicz K (2016) Anticonvulsant and procognitive properties of the non-imidazole histamine H3 receptor antagonist DL77 in male adult rats. Neuropharmacology 106:46–55

    Article  CAS  PubMed  Google Scholar 

  • Sánchez-Lemus E, Arias-Montaño JA (2004) Histamine H3 receptor activation inhibits dopamine D1 receptor-induced cAMP accumulation in rat striatal slices. Neurosci Lett 364:179–184

    Article  PubMed  CAS  Google Scholar 

  • Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22:565–572

    Article  CAS  PubMed  Google Scholar 

  • Schlicker E, Betz R, Göthert M (1988) Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex. Naunyn Schmiedebergs Arch Pharmacol 337:588–590

    Article  CAS  PubMed  Google Scholar 

  • Schlicker E, Fink K, Hinterthaner M, Göthert M (1989) Inhibition of noradrenaline release in the rat brain cortex via presynaptic H3 receptors. Naunyn Schmiedebergs Arch Pharmacol 340:633–638

    Article  CAS  PubMed  Google Scholar 

  • Schlicker E, Fink K, Detzner M, Göthert M (1993) Histamine inhibits dopamine release in the mouse striatum via presynaptic H3 receptors. J Neural Transm Gen Sect 93:1–10

    Article  CAS  PubMed  Google Scholar 

  • Schlicker E, Werthwein S, Zentner J (1999) Histamine H3 receptor-mediated inhibition of noradrenaline release in the human brain. Fundam Clin Pharmacol 13:120–122

    Article  CAS  PubMed  Google Scholar 

  • Schneider EH, Neumann D, Seifert R (2014a) Modulation of behavior by the histaminergic system: Lessons from H1R- and H2R-deficient mice. Neurosci Biobehav Rev 42:252–286

    Article  CAS  PubMed  Google Scholar 

  • Schneider EH, Neumann D, Seifert R (2014b) Modulation of behavior by the histaminergic system: Lessons from HDC-, H3R- and H4R-deficient mice. Neurosci Biobehav Rev 47:101–121

    Article  PubMed  CAS  Google Scholar 

  • Schwartz JC (2011) The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol 163:713–721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seifert R, Strasser A, Schneider EH, Neumann D, Dove S, Buschauer A (2013) Molecular and cellular analysis of human histamine receptor subtypes. Trends Pharmacol Sci 34:33–58

    Article  CAS  PubMed  Google Scholar 

  • Selivanova SV, Honer M, Combe F, Isensee K, Stark H, Krämer S, Schubiger PA, Ametamey SM (2012) Radioflurinated histamine H3 receptor antagonist as a potential probe for in vivo PET imaging: radiosynthesis and pharmacological evaluation. Bioorg Med Chem 20:2889–2896

    Article  CAS  PubMed  Google Scholar 

  • Simons FER (2004) Advances in H1-antihistamines. N Engl J Med 351:2203–2217

    Article  CAS  PubMed  Google Scholar 

  • Slater JW, Zechnich AD, Haxby DG (1999) Second-generation antihistamines. A comparative review. Drugs 57:31–47

    Article  CAS  PubMed  Google Scholar 

  • Stevens DR, Eriksson KS, Brown RE, Haas HL (2001) The mechanism of spontaneous firing in histamine neurons. Behav Brain Res 124:105–112

    Article  CAS  PubMed  Google Scholar 

  • Strange PG (2010) Use of the GTPγS ([35S]GTPγS and EuGTPγS) binding assay for analysis of ligand potency and efficacy at G protein-coupled receptors. Br J Pharmacol 161:1238–1249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sturman G, Freeman P, Meade HM, Seeley NA (1994) Modulation of the intracellular and H3-histamine receptors and chemically-induced seizures in mice. Agents Actions 41:C68–C69

    Article  CAS  PubMed  Google Scholar 

  • Szabo B, Schlicker E (2005) Effects of cannabinoids on neurotransmission. Handb Exp Pharmacol 168:327–365

    Article  CAS  Google Scholar 

  • Tabarean IV (2016) Histamine receptor signaling in energy homeostasis. Neuropharmacology 106:13–19

    Article  CAS  PubMed  Google Scholar 

  • Toyota H, Dugovic C, Koehl M, Laposky AD, Weber C, Ngo K, Wu Y, Lee DH, Yanai K, Sakurai E, Watanabe T, Liu C, Chen J, Barbier AJ, Turek FW, Fung-Leung WP, Lovenberg TW (2002) Behavioral characterization of mice lacking histamine H3 receptors. Mol Pharmacol 62:389–397

    Article  CAS  PubMed  Google Scholar 

  • Tozer MJ, Kalindjian SB (2000) Histamine H3 receptor antagonists. Exp Opin Ther Pat 10:1045–1055

    Article  CAS  Google Scholar 

  • Tuomisto L, Tacke U (1986) Is histamine an anticonvulsive inhibitory transmitter? Neuropharmacology 25:955–958

    Article  CAS  PubMed  Google Scholar 

  • Uguen M, Perrin D, Belliard S, Ligneau X, Beardsley PM, Lecomte JC (2013) Preclinical evaluation of the abuse potential of pitolisant, a histamine H3 receptor inverse agonist/antagonist compared with Modafinil. Br J Pharmacol 169:632–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • von Einsiedel RW, Roesch-Ely D, Diebold K, Sartor K, Mundt C, Bergemann N (2002) H2-histamine antagonist (famotidine) induced adverse CNS reactions with long-standing secondary mania and epileptic seizures. Pharmacopsychiatry 35:152–154

    Article  Google Scholar 

  • Weisler RH, Pandina GJ, Daly EJ, Cooper K, Gassmann-Mayer C, 31001074-ATT2001 Study Investigators (2012) Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder. CNS Drugs 26:421–434

    Google Scholar 

  • Wright T (2016) Menière’s disease. BMI Clin Evid 2016:pii: 0505

    Google Scholar 

  • Yanai K, Ryu JH, Sakai N, Takahashi T, Iwata R, Ido T, Murakami K, Watanabe T (1994) Binding characteristics of a histamine H3-receptor antagonist, [3H]S-methylthioperamide: comparison with [3H]Rα-methylhistamine binding to rat tissues. Jpn J Pharmacol 65:107–112

    Article  CAS  PubMed  Google Scholar 

  • Yawata I, Tanaka K, Nakagawa Y, Watanabe Y, Murashima YL, Nakano K (2004) Role of histaminergic neurons in development of epileptic seizures in EL mice. Brain Res Mol Brain Res 132:13–17

    Article  CAS  PubMed  Google Scholar 

  • Yokoyama H (2001) The role of central histaminergic neuron system as an anticonvulsive mechanism in developing brain. Brain Dev 23:542–547

    Article  CAS  PubMed  Google Scholar 

  • Yoshimoto R, Miyamoto Y, Shimamura K, Ishihara A, Takahashi K, Kotani H, Chen AS, Chen HY, Macneil DJ, Kanatani A, Tokita S (2006) Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes. Proc Natl Acad Sci 103:13866–13871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zlomuzica A, Viggiano D, De Souza Silva MA, Ishizuka T, Girone Carnevale UA, Ruocco LA, Watanabe T, Sadile AG, Huston JP, Dere E (2008) The histamine H1-receptor mediates the motivational effects of novelty. Eur J Neurosci 27:1461–1474

    Article  CAS  PubMed  Google Scholar 

  • Zlomuzica A, Ruocco LA, Sadile AG, Huston JP, Dere E (2009) Histamine H1 receptor knockout mice exhibit impaired spatial memory in the eight-arm radial maze. Br J Pharmacol 157:86–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zlomuzica A, Dere D, Dere E (2013) The histamine H1 receptor and recollection-based discrimination in a temporal order memory task in the mouse. Pharmacol Biochem Behav 111:58–63

    Article  CAS  PubMed  Google Scholar 

  • Zlomuzica A, Dere D, Binder S, De Souza Silva MA, Huston JP, Dere E (2016) Neuronal histamine and cognitive symptoms in Alzheimer’s disease. Neuropharmacology 106:135–145

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institut für Pharmakologie und Toxikologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany

    Eberhard Schlicker & Markus Kathmann

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  1. Eberhard Schlicker
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  2. Markus Kathmann
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Correspondence to Eberhard Schlicker .

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  1. Department of Molecular and Medical Pharmacology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Yuichi Hattori

  2. Institute of Pharmacology, Medical School of Hannover, Hannover, Germany

    Roland Seifert

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Schlicker, E., Kathmann, M. (2016). Role of the Histamine H3 Receptor in the Central Nervous System. In: Hattori, Y., Seifert, R. (eds) Histamine and Histamine Receptors in Health and Disease. Handbook of Experimental Pharmacology, vol 241. Springer, Cham. https://doi.org/10.1007/164_2016_12

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